Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

MATURA; PAMERA; Consortia; John C. Taylor; Tim Bongartz; Jonathan Massey; Borbala Mifsud; Athina Spiliopoulou; Ian C. Scott; Jianmei Wang; Michael Morgan; Darren Plant; Marco Colombo; Peter Orchard; Sarah Twigg; Iain B. McInnes; Duncan Porter; Jane E. Freeston; Jackie L. Nam; Heather J. Cordell; John D. Isaacs; Jenna L. Strathdee; Donna Arnett; Maria J.H. de Hair; Paul P. Tak; Stella Aslibekyan; Ronald F. van Vollenhoven; Leonid Padyukov; S. Louis Bridges; Costantino Pitzalis; Andrew P. Cope; Suzanne M.M. Verstappen; Paul Emery; Michael R. Barnes; Felix Agakov; Paul McKeigue; Taisei Mushiroda; Michiaki Kubo; Richard Weinshilboum; Anne Barton; Ann W. Morgan; Jennifer H. Barrett

doi:10.1038/s41397-018-0025-5

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

MATURA, PAMERA, Consortia, John C. Taylor, Tim Bongartz, Jonathan Massey, Borbala Mifsud, Athina Spiliopoulou, Ian C. Scott, Jianmei Wang, Michael Morgan, Darren Plant, Marco Colombo, Peter Orchard, Sarah Twigg, Iain B. McInnes, Duncan Porter, Jane E. Freeston, Jackie L. Nam, Heather J. CordellJohn D. Isaacs, Jenna L. Strathdee, Donna Arnett, Maria J.H. de Hair, Paul P. Tak, Stella Aslibekyan, Ronald F. van Vollenhoven, Leonid Padyukov, S. Louis Bridges, Costantino Pitzalis, Andrew P. Cope, Suzanne M.M. Verstappen, Paul Emery, Michael R. Barnes, Felix Agakov, Paul McKeigue, Taisei Mushiroda, Michiaki Kubo, Richard Weinshilboum, Anne Barton, Ann W. Morgan^*, Jennifer H. Barrett

^*Corresponding author for this work

Inflammation Biology

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

Abstract

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10⁻⁷ for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Original language	English
Pages (from-to)	1-11
Number of pages	11
Journal	Pharmacogenomics Journal
DOIs	https://doi.org/10.1038/s41397-018-0025-5
Publication status	E-pub ahead of print - 25 May 2018

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MATURA, PAMERA, Consortia, Taylor, J. C., Bongartz, T., Massey, J., Mifsud, B., Spiliopoulou, A., Scott, I. C., Wang, J., Morgan, M., Plant, D., Colombo, M., Orchard, P., Twigg, S., McInnes, I. B., Porter, D., Freeston, J. E., Nam, J. L., ... Barrett, J. H. (2018). Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients. Pharmacogenomics Journal, 1-11. Advance online publication. https://doi.org/10.1038/s41397-018-0025-5

@article{c0c171b917664e4e8ce1b0c5f80a6117,

title = "Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients",

abstract = "Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.",

author = "MATURA and PAMERA and Consortia and Taylor, {John C.} and Tim Bongartz and Jonathan Massey and Borbala Mifsud and Athina Spiliopoulou and Scott, {Ian C.} and Jianmei Wang and Michael Morgan and Darren Plant and Marco Colombo and Peter Orchard and Sarah Twigg and McInnes, {Iain B.} and Duncan Porter and Freeston, {Jane E.} and Nam, {Jackie L.} and Cordell, {Heather J.} and Isaacs, {John D.} and Strathdee, {Jenna L.} and Donna Arnett and {de Hair}, {Maria J.H.} and Tak, {Paul P.} and Stella Aslibekyan and {van Vollenhoven}, {Ronald F.} and Leonid Padyukov and Bridges, {S. Louis} and Costantino Pitzalis and Cope, {Andrew P.} and Verstappen, {Suzanne M.M.} and Paul Emery and Barnes, {Michael R.} and Felix Agakov and Paul McKeigue and Taisei Mushiroda and Michiaki Kubo and Richard Weinshilboum and Anne Barton and Morgan, {Ann W.} and Barrett, {Jennifer H.}",

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doi = "10.1038/s41397-018-0025-5",

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MATURA, PAMERA, Consortia, Taylor, JC, Bongartz, T, Massey, J, Mifsud, B, Spiliopoulou, A, Scott, IC, Wang, J, Morgan, M, Plant, D, Colombo, M, Orchard, P, Twigg, S, McInnes, IB, Porter, D, Freeston, JE, Nam, JL, Cordell, HJ, Isaacs, JD, Strathdee, JL, Arnett, D, de Hair, MJH, Tak, PP, Aslibekyan, S, van Vollenhoven, RF, Padyukov, L, Bridges, SL, Pitzalis, C, Cope, AP, Verstappen, SMM, Emery, P, Barnes, MR, Agakov, F, McKeigue, P, Mushiroda, T, Kubo, M, Weinshilboum, R, Barton, A, Morgan, AW & Barrett, JH 2018, 'Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients', Pharmacogenomics Journal, pp. 1-11. https://doi.org/10.1038/s41397-018-0025-5

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AU - MATURA

AU - PAMERA

AU - Consortia

AU - Taylor, John C.

AU - Bongartz, Tim

AU - Massey, Jonathan

AU - Mifsud, Borbala

AU - Spiliopoulou, Athina

AU - Scott, Ian C.

AU - Wang, Jianmei

AU - Morgan, Michael

AU - Plant, Darren

AU - Colombo, Marco

AU - Orchard, Peter

AU - Twigg, Sarah

AU - McInnes, Iain B.

AU - Porter, Duncan

AU - Freeston, Jane E.

AU - Nam, Jackie L.

AU - Cordell, Heather J.

AU - Isaacs, John D.

AU - Strathdee, Jenna L.

AU - Arnett, Donna

AU - de Hair, Maria J.H.

AU - Tak, Paul P.

AU - Aslibekyan, Stella

AU - van Vollenhoven, Ronald F.

AU - Padyukov, Leonid

AU - Bridges, S. Louis

AU - Pitzalis, Costantino

AU - Cope, Andrew P.

AU - Verstappen, Suzanne M.M.

AU - Emery, Paul

AU - Barnes, Michael R.

AU - Agakov, Felix

AU - McKeigue, Paul

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Weinshilboum, Richard

AU - Barton, Anne

AU - Morgan, Ann W.

AU - Barrett, Jennifer H.

PY - 2018/5/25

Y1 - 2018/5/25

N2 - Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

AB - Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

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U2 - 10.1038/s41397-018-0025-5

DO - 10.1038/s41397-018-0025-5

M3 - Article

AN - SCOPUS:85046847176

SN - 1470-269X

SP - 1

EP - 11

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

ER -

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

Abstract

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